Macrocyclic compounds (MCs) are of growing interest for inhibition of challenging drug targets. We consider what structural and physicochemical features could be relevant to the bioactivity of this compound class. Using these features, we performed Principal Component Analysis to map oral and non-oral macrocycle drugs and clinical candidates, and also commercially available synthetic MCs, in structure–property space. Our results show that oral MC drugs occupy defined regions that are distinct from those of the non-oral MC drugs; that none of the oral MC regions are effectively sampled by the synthetic MCs; and furthermore, we identify underexplored regions within this MC chemical space. We identify 13 properties that can be used to design synthetic MCs that sample regions overlapping with oral MC drugs. We also retrospectively analyze the MC kinase inhibitor drugs, that compose one of the regions occupied by oral MC drugs, to highlight properties of macrocycles advantageous for drug design. Collectively, the results advance our understanding of what molecular features are associated with bioactive and orally bioavailable MCs and illustrate an approach by which synthetic chemists can better evaluate MC designs.

Defining and navigating macrocycle chemical space

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